Abstract
Alzheimer’s disease (AD) is a progressive brain disorder and age-related disease characterised by abnormal accumulation of β-amyloid (Aβ). The development of drugs to combat AD is hampered by the lack of therapeutically-active molecules able to cross the blood-brain barrier (BBB). It is agreed that specifically-designed carriers, such as dendrimers, could support the drug penetration across the BBB. The aim of this study was to design biocompatible and biodegradable dendrimeric delivery systems able to carry Flurbiprofen (FP), as drug for AD treatment, across the BBB and liberate it at the target tissue. These dendrons were synthesised using solid-phase peptide synthesis method and characterised by mass spectrometry and fourier-transform infrared spectroscopy (FTIR). The results revealed successful synthesis of dendrons having FP been integrated during the synthesis at their branching ends. Cytotoxicity assays demonstrated the biocompatibility of the delivery systems, whereas HPLC analysis showed high percentages of permeability across an in vitro BBB model for FP-integrated dendrons. Results also revealed the efficiency of drug conjugates on the γ-secretase enzyme in target cells with evidence of eventual drug release by hydrolysis of the carrier. This study demonstrates that the coupling of FP to dendrimeric delivery systems can successfully be achieved during the synthesis of the poly(epsilon-lysine) macromolecules to improve the transport of the active drug across the BBB.
Highlights
Alzheimer’s disease (AD) is an age-related and neurodegenerative disease (ND) characterised by gradual impairment in memory
The mass spectra demonstrated the successful loading of FP to both G0- and G1-dendron with peaks corresponding to the expected molecular weight (MW) (745.33 Da for G0K-FP and 1454.7 Da for G1K-FP) as presented in Figure 1a,b, respectively
fourier-transform infrared spectroscopy (FTIR) analysis revealed a shift in peaks due to the formation of an amide linkage at 3200 cm−1 and 1640 cm−1 that confirm the attachment of drug to both G0- and G1-dendrons (Figure 2)
Summary
Alzheimer’s disease (AD) is an age-related and neurodegenerative disease (ND) characterised by gradual impairment in memory. AD is typified by plaque accumulation of abnormally folded extracellular deposits of Aβ-amyloid (Aβ) and tau proteins in the brain [2]. Aβ species are generated from the amyloid precursor protein (APP) through proteolytic cleavages initiated by β-secretase (BACE-1), with fragments being further cleaved by γ-secretase. These fragments of APP are made up of different Aβ isoforms depending on the number of amino acids [3]. The most prevalent variant isoforms of Aβ are Aβ40 and Aβ42 which, in AD, form dense clumps of deposits surrounding neurons and giving rise to senile plaques of ND [4]
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